Macrolide antibiotics

ABSTRACT

The present invention relates to 11,12γ lactone ketolides of formula (I), wherein R, R 1 , R 2  and R 3  are as defined herein and pharmaceutically acceptable salts and solvates thereof, to process for their preparation and their use in therapy or prophylaxis of systemic or topical bacterial infections in a human or animal body.

[0001] The present invention relates to novel semi-synthetic macrolideshaving antibacterial activity. More particularly this invention relatesto 11,12 γ lactone ketolides, to processes for their preparation, tocompositions containing them and to their use in medicine.

[0002] EP 1114826 inter alia generically discloses macrolide compoundsof formula (A) having antibacterial activity

[0003] wherein R₁ is hydrogen or a hydroxyl protecting group; R₄ isinter alia an optionally substituted C₁₋₁₀ alkyl, X₁ is inter aliaoxygen, X₂ is inter alia CH₂, Y is NH, O or S, R₅ is inter alia C(O) andR₁₃ is hydrogen or halo.

[0004] We have now found novel 11,12 γ lactone ketolides havingantibacterial activity.

[0005] Thus, the present invention provides compounds of general formula(I)

[0006] wherein

[0007] R is hydrogen, cyano or NR₄R₅;

[0008] R₁ is XR₆;

[0009] R₂ is hydrogen or a hydroxyl protecting group;

[0010] R₃ is hydrogen or halogen;

[0011] R₆ is selected from:

[0012] optionally substituted phenyl;

[0013] optionally substituted 5 or 6 membered heteroaryl in which the5-membered heteroaryl contains at least one heteroatom selected fromoxygen, sulphur or nitrogen and the 6-membered heteroaryl group containsfrom 1 to 3 nitrogen atoms,

[0014] optionally substituted 5-6 membered heterocyclic,

[0015] optionally substituted 9 to 10 membered fused bicycliccarbocyclic; or

[0016] R₆ is an optionally substituted 9 or 10 membered fused bicyclicheterocyclic having at least one heteroatom selected from oxygen,sulphur or nitrogen;

[0017] X is a C₁₋₁₀ alkylene, a C₃₋₁₀ alkenylene or a C₃₋₁₀ alkynylenechain wherein said chains are:

[0018] i) optionally interrupted by a bivalent radical group selectedfrom —N(R₅)—, —C(O)—, —S(O)n-, —N(R₅)C(O)—, —C(O)N(R₅)—,

[0019] ii) optionally substituted by one or two groups selected from:

[0020] C₁₋₄ alkyl, oxo, C₁₋₄ alkoxy, halogen, cyano, phenoxy, hydroxy,NR₄R₅;

[0021] R₄ is hydrogen, C₁₋₄ alkyl or C(O)R₅;

[0022] R₅ is hydrogen or C₁₋₄ alkyl;

[0023] n is 0 or an integer from 1 to 2;

[0024] and pharmaceutically acceptable salts and solvates thereof.

[0025] A further embodiment of the invention provides compounds ofgeneral formula (I) wherein

[0026] R is hydrogen, cyano or NR₄R₅;

[0027] R₁ is XR₆;

[0028] R₂ is hydrogen or a hydroxyl protecting group;

[0029] R₃ is hydrogen or halogen;

[0030] R₆ is selected from:

[0031] optionally substituted phenyl;

[0032] optionally substituted 9 to 10 membered aromatic fused bicycliccarbocyclic ring;

[0033] optionally substituted 5 or 6 membered heteroaryl in which the5-membered heteroaryl contains at least one heteroatom selected fromoxygen, sulphur or nitrogen and the 6-membered heteroaryl group containsfrom 1 to 3 nitrogen atoms;

[0034] R₆ is optionally substituted fused bicyclic heteroaryl groupscontaining 9 or 10 ring members having at least one heteroatom selectedfrom oxygen, sulphur or nitrogen;

[0035] X is a group selected from:

[0036] C₁₋₆ alkyl, optionally substituted by one or two groups selectedfrom a C₁₋₄ alkoxy, hydroxy or by NR₄R₅;

[0037] C₃₋₆ alkenyl group optionally substituted by one or two groupsselected from C₁₋₄ alkoxy, a halogen, a hydroxy or by a NR₄R₅ group;

[0038] C₃₋₆ alkynyl;

[0039] (CH₂)pY(CH₂)q wherein Y is selected from CO, S(O)n, NR₅,N(R₅)C(O) or C(O)N(R₅);

[0040] R₄ is hydrogen, C₁₋₄ alkyl or C(O)R₅;

[0041] R₅ is hydrogen or C₁₋₄ alkyl;

[0042] p is 0 or an integer from 1 to 4; q is 0 or an integer from 1 to5; with the proviso that the sum of p and q is an integer from 0 to 5; nis 0 or an integer from 1 to 2; provided that when Y is NR₆, S(O)n orN(R₅)C(O), p is not 0 or 1; and pharmaceutically acceptable salts andsolvates thereof.

[0043] Suitable pharmaceutically acceptable salts of the compounds ofgeneral formula (I) include acid addition salts formed withpharmaceutically acceptable organic or inorganic acids, for examplehydrochlorides, hydrobromides, sulphates, alkyl- or arylsulphonates(e.g. methanesulphonates or p-toluenesulphonates), phosphates, acetates,citrates, succinates, tartrates, fumarates and maleates.

[0044] The compound of formula (I) and salts thereof may form solvatesand the invention includes all such solvates. The solvates may, forexample, be hydrates.

[0045] References hereinafter to a compound according to the inventioninclude both compounds of formula (I) and their pharmaceuticallyacceptable acid addition salts together with pharmaceutically acceptablesolvates.

[0046] The compound of formula (I) and salts thereof may form solvates(e.g. hydrates) and the invention includes all such solvates.

[0047] In the general formula (I) as drawn, the solid wedge shaped bondindicates that the bond is above the plane of the paper. The broken bondindicates that the bond is below the plane of the paper.

[0048] It will be appreciated by those skilled in the art that thecompounds of formula (I) when R is not hydrogen contain further onechiral centre (namely the carbon atom shown as 21 in formula (I)) andthis may be represented by the formulae (1a) and (1b).

[0049] The configuration for the carbon atom shown as 21 in formula 1ais hereinafter referred to as the β configuration and in formula 1b asthe α configuration.

[0050] It is to be understood that the two diastereoisomers (1a, 1b) andmixtures thereof are encompassed within the scope of the presentinvention.

[0051] Compounds wherein R₂ represents a hydroxyl protecting group arein general intermediates for the preparation of other compounds offormula (I).

[0052] Compounds wherein R₂ represents a hydroxyl protecting group arein general intermediates for the preparation of other compounds offormula (I).

[0053] When the group OR₂ is a protected hydroxyl group this is anon-toxic protecting group, conveniently OR₂ is an acyloxy group (i.e.acetoxy or benzyloxy).

[0054] The term C₁₋₄ alkyl as used herein as a group or a part of thegroup refers to a straight or branched alkyl group containing from 1 to4 carbon atoms; examples of such groups include methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl and tert-butyl.

[0055] The term C₁₋₁₀ alkylene chain refers to straight or branchedchain containing from 1 to 10 carbon atoms examples of such groupinclude, but are not limited to methylene, ethylene, propylene,isopropylene, n-butylene, isobutylene, tert-butylene, pentylene,n-heptylene, n-octylene, n-nonylene and n-decylene.

[0056] The term C₃₋₁₀ alkenylene chain refers to a straight or branchedalkylene chain containing from 3 to 12 carbon atoms and having at leastone double bond; examples of such groups include 2-propenylene,1-propenylene, isopropenylene, 2-butenylene, 2-pentenylene, 2-hexenyleneand the like.

[0057] The term C₃₋₁₀ alkynylene chain refers to a straight or branchedalkylene chain containing from 3 to 12 carbon atoms and having at leastone triple bond; examples of such groups include 2-propynylene,1-propynylene, isopropynylene, 2-butynylene, 2-pentynylene, 2-hexenyleneand the like.

[0058] The term halogen refers to a fluorine, chlorine, bromine oriodine atom.

[0059] Examples of 5 or 6 membered heteroaryl group according to theinvention include furanyl, thiophenyl, pyrrolyl, imidazolyl, thiazolyl,oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl,1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-triazolyl,1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-oxadiazolyl,1,2,5-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4oxadiazolyl, 1,2,5-triazinyl or 1,3,5-triazinyl and the like.

[0060] The term 9 to 10 membered fused bicyclic heterocyclic grouprefers to a 5,6/6,5 or 6,6 bicyclic ring system, containing at least oneheteroatom selected from oxygen, sulphur or nitrogen, which may besaturated, unsaturated or aromatic. The term 9 to 10 membered fusedbicyclic heterocyclic group also refers to a phenyl fused to one 5 or 6membered heterocyclic group. Example of such groups includebenzofuranyl, benzothiophenyl, indolyl, benzoxazolyl,3H-imidazo[4,5-c]pyridin-yl, dihydrophthazinyl,1H-imidazo[4,5-c]pyridin-1-yl, imidazo[4,5-b]pyridyl, 1,3benzo[1,3]dioxolyl, 2H-chromanyl, isochromanyl, 5-oxo-2,3dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidyl, 1,3-benzothiazolyl, 1,4,5,6tetrahydropyridaziyl, 1,2,3,4,7,8 hexahydropteridinyl,2-thioxo2,3,6,9-tetrahydro-1H-purin-8-yl, 3,7-dihydro-1H-purin-8-yl, 3,4dihydropyrimidin-1-yl, 2,3-dihydro-1,4-benzodioxinyl,benzo[1,3]dioxolyl, 2H-chromenyl, chromanyl, 3,4-dihydrophthalazinyl,2,3 dihydro-1H-indolyl, 1,3-dihydro-2H-isoindol-2-yl, 2,4,7-trioxo-1,2,3,4,7,8-hexahydropteridinyl, thieno[3,2-d]pyrimidinyl,4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidinyl, 1,3dimethyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1H-purinyl, 1,2dihydroisoquinolinyl, 2-oxo-1,3-benzoxazolyl,2,3-dihydro-5H-1,3-thiazolo[3,2-a]pyrimidinyl,5,6,7,8-tetrahydro-quinazolinyl, 4-oxochromanyl, 1,3-benzothiazolyl,benzimidazolyl, benzotriazolyl, purinyl, furylpyridyl,thiophenylpyrimidyl, thiophenylpyridyl, pyrrolylpiridyl,oxazolylpyridyl, thiazolylpiridyl, 3,4 dihydropyrimidin-1-ylimidazolylpiridyl, quinoliyl, isoquinolinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pyrazolyl[3,4]pyridine, 1,2 di hydroisoquinolinyl,cinnolinyl, 2,3dihydro-benzo[1,4]dioxin-6-yl,4,5,6,7-tetrahydro-benzo[b]thiophenyl-2-yl, 1,8naphthyridinyl,1,6naphthyridinyl, 3,4dihydro-2H-1,4-benzothiazine,4,8-Dihydroxy-quinolinyl, 1-oxo-1,2-dihydro-isoquinolinyl or4-phenyl-[1,2,3]thiadiazolyl and the like.

[0061] The term 9 to 10 membered fused bicyclic carbocyclic group refersto a 5,6/6,5 or 6,6 bicyclic carbocyclic ring system which may besaturated, unsaturated or aromatic. It also refers to a phenyl fused toone 5 or 6 membered saturated or unsaturated carbocyclic group. Examplesof such groups include naphthyl, 1,2,3,4 tetrahydronaphthyl, indenyl orindanyl and the like.

[0062] When R₆ is a substituted phenyl or a substituted 5 or 6 memberedheteroaryl group this refers to a phenyl or a 5 or 6 membered heteroarylgroup which is substituted by 1 to 2 groups, which may be the same ordifferent, selected from (CH₂)_(r)R₇ group wherein r is zero or aninteger from 1 to 4 and R₇ is selected from:

[0063] hydrogen;

[0064] halogen;

[0065] C₁₋₄alkoxy;

[0066] hydroxy;

[0067] cyano;

[0068] nitro;

[0069] trifluoromethyl;

[0070] carboxy;

[0071] NR₄R₅;

[0072] CONR₄R₅;

[0073] NHCOR₈ wherein R₈ is C₁₋₄alkyl phenyl, 5 membered heteroarylcontaining at least 1 heteroatom selected from oxygen, sulphur ornitrogen or 6-membered heteroaryl group containing at least 1 nitrogenatoms;

[0074] NR₅CONR₈R₅;

[0075] NHS(O₂)R₉ (wherein R₉ is C₁₋₄alkyl or phenyl);

[0076] S(O)_(n)R₈ (wherein n is 0 or an integer from 1 to 2);

[0077] C₁₋₄ alkanoyl amino;

[0078] phenyl (optionally substituted by halogen, C₁₋₄alkoxy or NR₄R₅);

[0079] phenoxy;

[0080] 5-membered heteroaryl containing at least 1 heteroatoms selectedfrom oxygen, sulphur or nitrogen and a 6-membered heteroaryl groupcontaining at least 1 nitrogen atom.

[0081] When R₆ is an optionally substituted 9 to 10 fused bicyclicheteroaryl group or substituted 9 to 10 membered fused bicycliccarbocyclic ring, such groups are optionally substituted by one to 2substituents which may be the same or different and selected from alkyl,halogen, cyano, nitro, trifluoromethyl and NR₄R₅.

[0082] When X is a C₁₋₁₀ alkylene, a C₃₋₁₀ alkenylene or a C₃₋₁₀alkynylene chain which is interrupted by a bivalent radical groupselected from —N(R₅)—, —C(O)—, —S(O)n-, —N(R₅)C(O)—, —C(O)N(R₅)—, thisrefers for example to —C₁₋₁₀alkylene-N(R₅)—, C₁₋₁₀ alkylene-C(O),C₁₋₁₀alkylene-S(O)n-, C₁₋₁₀ alkylene-N(R₅)C(O)—, C₁₋₁₀alkylene-C(O)N(R₅)—,C₃₋₁₀alkenylene-N(R₅)—,C₃₋₁₀alkenylene-C(O)—, C₃₋₁₀alkenylene-S(O)n-, C₃₋₁₀ alkenylene-N(R₅)C(O)—, C₃₋₁₀alkenylene-C(O)N(R₅)—, C₃₋₁₀alkynylene-N(R₅)—, C₃₋₁₀alkynylene-C(O)—,C₃₋₁₀alkynylene-S(O)n-, C₃₋₁₀alkynylene-N(R₅)C(O)—, C₃₋₁₀alkynylene-C(O)N(R₅), or this refers to a C₁₋₁₀ alkylene, a C₃₋₁₀alkenylene or a C₃₋₁₀ alkynylene chain containing a bivalent radicalgroup selected from:

[0083] —N(R₅)—, —C(O)—, —S(O)n-, —N(R₅)C(O)—, —C(O)N(R₅)—.

[0084] When X is an optionally substituted C₁₋₁₀ alkylene, C₃₋₁₀alkenylene or C₃₋₁₀ alkynylene interrupted by a bivalent radicalselected from —N(R₅)—, —S(O)n-, —N(R₅)C(O)— said bivalent radicals arepreferably linked the oxygen atom by an optionally substituted alkylenechain containing at least two carbon atoms.

[0085] When X is an optionally substituted C₃₋₁₀ alkenylene, preferablythis chain contains one double bond at the two terminal carbon atoms ofthe chain.

[0086] When X is an optionally substituted C₃₋₁₀ alkenylene which isinterrupted by a bivalent radical group selected from —N(R₅)—, —C(O)—,—S(O)n-, —N(R₅)C(O)—, —C(O)N(R₅—, said bivalent radicals are preferablylinked to the double bond by an optionally substituted alkylene chaincontaining at least one carbon atom.

[0087] When X is an optionally substituted C₃₋₁₀ alkynylene, preferablythis chain contains one triple bond at the two terminal carbon atoms ofthe chain.

[0088] When X is an optionally substituted C₃₋₁₀ alkynylene which isinterrupted by a bivalent radical group selected from —N(R₅)—, —C(O)—,—S(O)n-, —N(R₅)C(O)—, —C(O)N(R₅)—, said bivalent radicals are preferablylinked to the triple bond by an optionally substituted alkylene chaincontaining at least one carbon atom.

[0089] A preferred group of compounds of formula (I) are those in whichthe carbon atom shown as 21 is in the β configuration.

[0090] R₂ is preferably hydrogen.

[0091] R₃ is preferably hydrogen or fluorine.

[0092] R₄ and R₅ are preferably hydrogen.

[0093] R₆ is preferably phenyl, quinolinyl, pyridinyl-imidazolyl orpyridinyl-4-thiazolyl.

[0094] X is preferably a C₁₋₆ alkylene or C₃₋₆ alkenylene chain.

[0095] A preferred group of compounds of formula (I) is that wherein Xis a C₁₋₆ alkylene or C₃₋₆ alkenylene chain, R₆ is a group selected fromphenyl, quinolinyl, pyridyl-imidazolyl, pyridyl-4thiazolyl and R₂, R₃,R₄ and R₅ are hydrogen.

[0096] Particularly preferred compounds of the invention are selectedfrom:

[0097](11S,21R)3-Decladinosyl-11,12-dideoxy-6-O-[(quinolin-3-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-(cyano)methylene]-erythromycinA;

[0098](11S)3-Decladinosyl-11,12-dideoxy-6-O-[(quinolin-3-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-methylene]-erythromycinA;

[0099](11S,21R)-3-Decladinosyl-11,12-dideoxy-6-O-[(quinolin-5-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA;

[0100](11S,21R)-3-Decladinosyl-11,12-dideoxy-6-O-[(quinolin-6-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA;

[0101](11S,21R)-3-Decladinosyl-11,12-dideoxy-6-O-[(quinolin-7-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA;

[0102](11S,21R)-3-decladinosyl-11,12-dideoxy-6-O-[(quinolin-5-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-methylene]-erythromycinA;

[0103](11S,21R)-3-decladinosyl-11,12-dideoxy-6-O-[(quinolin-6-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-methylene]-erythromycinA.

[0104] Compounds according to the invention also exhibit a broadspectrum of antibacterial activity against a wide range of clinicalpathogenic microorganisms.

[0105] For example, using a standard microtiter broth serial dilutiontest, compounds of the invention have been found to exhibit usefullevels of activity against a wide range of pathogenic microorganisimsincluding strains of Staphylococcus aureus, Streptopococcus pneumoniae,Moraxella catarrhalis, Streptococcus pyogenes, Haemophilus influenzae.

[0106] The compounds of the invention may therefore be used for treatinga variety of diseases caused by pathogenic bacteria in human beings andanimals.

[0107] Thus, according to another aspect of the present invention, weprovide a compound of formula (I) or a physiologically acceptable saltthereof for use in the therapy in a human or animal subject.

[0108] According to a further aspect of the invention we provide the useof a compound of formula (I) or a physiologically acceptable saltthereof for the manufacture of a therapeutic agent for the treatment ofsystemic or topical bacterial infections in a human or animal body.

[0109] According to a yet further aspect of the invention we provide amethod of treatment of the human or non-human animal body to combatbacterial infections which method comprises administering to the body aneffective amount of a compound of formula (I) or a physiologicallyacceptable salt thereof.

[0110] The term treatment is also meant to include prophylaxis.

[0111] While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation.

[0112] The compounds of the invention may be formulated foradministration in any convenient way for use in human or veterinarymedicine and the invention therefore includes within its scopepharmaceutical compositions comprising a compound of the inventionadapted for use in human or veterinary medicine. Such compositions maybe presented for use in conventional manner with the aid of one or moresuitable carriers or excipients. The compositions of the inventioninclude those in a form especially formulated for parenteral, oral,buccal, rectal, topical, implant, ophthalmic, nasal or genito-urinaryuse.

[0113] The compounds according to the invention may be formulated foruse in human or veterinary medicine by injection (e.g. by intravenousbolus injection or infusion or via intramuscular, subcutaneous orintrathecal routes) and may be presented in unit dose form, in ampoules,or other unit-dose containers, or in multi-dose containers, if necessarywith an added preservative. The compositions for injection may be in theform of suspensions, solutions, or emulsions, in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilising, solubilising and/or dispersing agents. Alternatively theactive ingredient may be in sterile powder form for reconstitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

[0114] The compounds of the invention may also be presented for human orveterinary use in a form suitable for oral or buccal administration, forexample in the form of solutions, gels, syrups, mouth washes orsuspensions, or a dry powder for constitution with water or othersuitable vehicle before use, optionally with flavouring and colouringagents. Solid compositions such as tablets, capsules, lozenges,pastilles, pills, boluses, powder, pastes, granules, bullets or premixpreparations may also be used. Solid and liquid compositions for oraluse may be prepared according to methods well known in the art. Suchcompositions may also contain one or more pharmaceutically acceptablecarriers and excipients which may be in solid or liquid form.

[0115] The compounds of the invention may also be administered orally inveterinary medicine in the form of a liquid drench such as a solution,suspension or dispersion of the active ingredient together with apharmaceutically acceptable carrier or excipient.

[0116] The compounds of the invention may also, for example, beformulated as suppositories, e.g. containing conventional suppositorybases for use in human or veterinary medicine or as pessaries e.g.containing conventional pessary bases.

[0117] The compounds according to the invention may be formulated fortopical administration, for use in human and veterinary medicine, in theform of ointments, creams, gels, lotions, shampoos, powders, (includingspray powders), pessaries, tampons, sprays, dips, aerosols, drops (e.g.eye ear or nose drops) or pour-ons.

[0118] Aerosol sprays are conveniently delivered from pressurised packs,with the use of a suitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas.

[0119] For topical administration by inhalation the compounds accordingto the invention may be delivered for use in human or veterinarymedicine via a nebuliser.

[0120] The pharmaceutical compositions for topical administration mayalso contain other active ingredients such as corticosteroids orantifungals as appropriate.

[0121] The compositions may contain from 0.01-99% of the activematerial. For topical administration, for example, the composition willgenerally contain from 0.01-10%, more preferably 0.01-1% of the activematerial.

[0122] For systemic administration the daily dose as employed for adulthuman treatment it will range from 2-100 mg/kg body weight, preferably5-60 mg/kg body weight, which may be administered in 1 to 4 daily doses,for example, depending on the route of administration and the conditionof the patient. When the composition comprises dosage units, each unitwill preferably contain 200 mg to 1 g of active ingredient

[0123] The duration of treatment will be dictated by the rate ofresponse rather than by arbitrary numbers of days.

[0124] Compounds of general formula (I) and salts thereof may beprepared by general method outlined hereinafter. In the followingdescription, the groups R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, q or r and Xhave the meanings defined for the compounds of formula (I) unlessotherwise stated.

[0125] Compounds of formula (I) in which R is hydrogen may be preparedby decarboxylation of a compound of formula (II), wherein R_(1a) has themeaning defined above for formula (I) for R₁ or is a group convertiblethereto, R₁₀ is a cladinose derivative of formula (III) or hydroxy, R₁₁is hydrogen or R₁₁ together R₁₀ is an oxygen atom, followed if required,subjecting the resulting compound to one or more of the followingoperations: a) conversion of the group R_(1a) into the group R₁; b)hydrolysis of the cladinose derivative (III); c) conversion of the3-hydroxy group into the 3-oxo and d) removal of the protecting groupR₂.

[0126] The decarboxylation may be carried out in the presence of alithium salt such as lithium chloride, preferably in an organic solventsuch as dimethylsulphoxide.

[0127] Compounds of formula (I), wherein R is cyano, may be prepared bycyclisation of chlorine derivatives (IV) wherein R_(1a), R₁₀ and R₁₁have the meaning as defined for compounds of formula (II)

[0128] followed, if required, subjecting the resulting compound to oneor more of the following operations: a) conversion of the group R_(1a)into the group R₁; b) hydrolysis of the cladinose derivative (III); c)conversion of the 3-hydroxy group into the 3-oxo and d) removal of theprotecting group R₂.

[0129] The cyclisation of a compound of formula (IV) is carried out inthe presence of potassium cyanide and conveniently in the presence of asolvent such as a N—N dimethylformamide. Alternatively compounds offormula (I) wherein R is hydrogen, may be prepared by elimination ofcyano group by treatment of compounds of formula(IVa) with aluminumoxide

[0130] wherein R_(1a), R₁₀ and R₁₁ have the meaning as defined forcompounds of formula (II), followed, if required, subjecting theresulting compound to one or more of the following operations: a)conversion of the group R_(1a) into the group R₁; b) hydrolysis of thecladinose derivative (III); c) conversion of the 3-hydroxy group intothe 3-oxo and d) removal of the protecting group R₂.

[0131] Compounds of formula (I), wherein R is NR₄R₅, R₄ is C₁₋₄alkyl andR₅ is hydrogen or C₁₋₄alkyl, may be prepared by treating amino compoundsof formula (V) in which R_(1a), R₁₀ and R₁₁ have the meaning defined informula (II)

[0132] with a suitable alkylating agent of formula L-R₄ (VI) wherein R₄is C₁₋₄ alkyl and L is a suitable leaving group such as a halogen (e.g.chlorine, bromine or iodine) or a sulfonyl (e.g. tosyl, methansulfonyl),in the presence of a base, followed, if required, subjecting theresulting compound to one or more of the following operations: a)conversion of the group R_(1a) into the group R₁; b) hydrolysis of thecladinose derivative (II); c) conversion of the 3-hydroxy group into the3-oxo and d) removal of the protecting group R₂.

[0133] Compounds of formula (I), wherein R is NR₄R₅, R₄ is C(O)R₅, maybe prepared by treating amino compounds of formula (V) in which R₁₀ andR₁₁ have the meaning defined in formula (II), by acylation reaction withan activated derivative of the acid HO(O)CR₅ (VI a), followed ifrequired, subjecting the resulting compound to one or more of thefollowing operations: a) conversion of the group R_(1a) into the groupR₁; b) hydrolysis of the cladinose derivative (II); c) conversion of the3-hydroxy group into the 3-oxo and d) removal of the protecting groupR₂.

[0134] Suitable activated derivatives of the carboxyl group or thesulphonic acid include the corresponding acyl halide, mixed anhydride oractivated ester such as a thioester or a pentafluoroester.

[0135] The reaction is preferably carried out in the presence of a basesuch as a tertiary amine e.g. triethylamine or pyridine in a solventsuch as a halohydrocarbon e.g. dichloromethane at a temperature withinthe range 0° to 50° C.

[0136] Compounds of formula (I), wherein R is NH₂ may be prepared byintramolecular Michael reaction of compounds of formula (VII) whereinR₁₂ is a suitable nitrogen protecting group, R_(1a), R₁₀ and R₁₁ havethe meaning defined in formula (II), in the presence of an organic basesuch as 1,8-diazabicyclo[5.4.0]undec-7-ene, followed, if required,subjecting the resulting compound to one or more of the followingoperations: a) conversion of the group R_(1a) into the group R₁; b)hydrolysis of the cladinose derivative (II); c) conversion of the3-hydroxy group into the 3-oxo and d) removal of the protecting groupsR₂ and R₁₂.

[0137] (VIII)

[0138] The reaction conveniently takes place in an aprotic polar solventsuch as acetonitrile, dimethylformamide or an aqueous mixture thereof,followed by removal of the nitrogen protecting group R₁₂.

[0139] Suitable nitrogen protecting group R₁₂ for use in this reactioninclude diarylmethylidene such as diphenylmethylidene.

[0140] When R_(1a) is a group convertible into the group R₁ this issuitably C₁₋₁₀ alkyl, C₃₋₁₀ alkenyl or C₃₋₁₀ alkynyl.

[0141] The cladinose derivative of formula (III) may be removed bytreatment with an organic or inorganic acid. An example of a suitableinorganic acid is hydrochloride. The reaction is carried out in thepresence of water or an organic solvent such tetrahydrofuran,dichloromethane or mixture thereof.

[0142] The conversion of the 3-hydroxy group into the 3-oxo may beperformed by oxidation reaction using a modified Moffatt-Pfitznerprocedure.

[0143] Suitable oxidizing agents include N,N-Dimethylaminopropyl-3-ethylcarbodiimide—dimethylsulfoxide. The reaction is suitably carried out inthe presence of pyridiniumtrifluoro acetate in a chlorinated solventsuch as methylene chloride at −10° C. to 25° C.

[0144] In a further embodiment, the oxidation may be carried out usingDess Martin periodinane reagent.

[0145] Compounds of formula (I) wherein X is a C₃₋₁₀ alkenylene chainand R₆ is selected from optionally substituted phenyl, optionallysubstituted 5 or 6 membered heteroaryl, optionally substituted 9 or 10membered fused bicyclic aromatic heterocyclic or optionally substituted9 to 10 membered aromatic fused bicyclic carbocyclic may be prepared byHeck reaction of compounds of formula (VIII),

[0146] wherein R₁₀ and R₁₁ have the meaning defined in formula (II), pis an integer from 1 to 8 with a ZR₆ (IX) compound wherein Z is achloride, bromide or triflate.

[0147] In one embodiment of this process the reaction may be carried outusing a catalytic amount of a Palladium (0) complex such astetrakis(triaryl phosphine)palladium (e.g.tetrakis(tri-o-tolylphosphine)palladium or tetrakis(triphenylphosphine)palladium).

[0148] The reaction is conveniently carried out in an aprotic solventsuch as acetonitrile, dimethylformamide or toluene at a temperature withthe range of 60° C. to 150° C.

[0149] Compounds of formula (I), wherein X is a C₃₋₁₀ alkenylene chainand R₆ is selected from optionally substituted phenyl, optionallysubstituted 5 or 6 membered heteroaryl, optionally substituted 9 or 10membered fused bicyclic aromatic heterocyclic or optionally substituted9 to 10 membered aromatic fused bicyclic carbocyclic, may be prepared bySuzuki reaction of the compounds (X),

[0150] wherein R₁₀ and R₁₁ have the meaning defined in formula (II) andp is an integer from 1 to 8, with a boronic acid derivativeR₆B(OH)₂(Xa), wherein R6 has the meaning defined in formula (IX)

[0151] In one embodiment of this process the reaction may be carried outusing a catalytic amount of a Palladium (0) complex such astetrakis(triaryl phosphine)palladium (e.g.tetrakis(tri-o-tolylphosphine)palladium or tetrakis(triphenylphosphine)palladium).

[0152] The reaction is conveniently carried out in an aprotic solventsuch as acetonitrile, dimethylformamide or toluene at a temperature withthe range of 60° C. to 150° C.

[0153] Compounds of formula (I), X is C₃₋₁₀ alkylene optionallysubstituted as defined in formula (I), may be prepared by reduction ofthe compound of formula (I) wherein X is C₃₋₁₀ alkenylene.

[0154] The reduction may be carried out using hydrogen in the presenceof a metal catalyst e.g. palladium on a suitable support e.g. carbon oralumina.

[0155] Compounds of formula (I) or compounds of formulas (II), (IV),(IVa) or (V), wherein R_(1a) is XR₆, wherein X is (CH2)_(r)C(O)(CH2)q, ris an integer from 1 to 4 and q is an integer from 6 to 9, may beprepared by ozonolysis of a compound of formula (XI), wherein followedby treatment the corresponding aldehyde (XII), with an organo metalicderivative of formula (XIII) M(CH₂)qR₆ (XIII), in which M is a metal,and by oxidation of the alcohol (XIII) to the keto group (XIV) accordingto the following reaction sequence.

[0156] Examples of suitable metal which may be used in this reactioninclude lithium, zinc or magnesium.

[0157] The reaction with compound (XII) is suitably carried out in anaprotic solvent such as toluene, tetrahydrofuran at a temperatureranging from −70° to −20° C.

[0158] The oxidation reaction may be carried out using conventionaloxidising agents known in the art for converting a secondary alcoholinto a ketone. Thus for example the oxidation may be carried out usingpyridinium chlorochromate or oxalyl chloride and dimethylsulphoxide. Thereaction is preferably carried out in a solvent such as methylenechloride.

[0159] Compounds of formula (I) or compounds of formulas (II), (I),(IVa) or (V), wherein R_(1a) is XR₆, wherein X is(CH2)_(r)C(O)N(R₅)(CH2)_(q), in which r is an integer from 1 to 4 toform and q is an integer from 6 to 9, may be prepared by oxidation ofaldehyde (XII) to the corresponding carboxylic acid (XV), followed byreaction with the amine (XVI) in the presence of an activating agent.

[0160] A suitable activating agent of the carboxyl group is for exampleacyl halide.

[0161] Compounds of formula (I) or compounds of formulas (II), (IV),(IVa) or (V), wherein R_(1a) is XR₆, wherein X is(CH2)_(r)N(R₅)(CH2)_(q), in which r is an integer from 1 to 4, may beprepared by reaction of aldehyde (XII), wherein q is 2 or 3, with aminecompounds NHR₅(CH2)_(q)R₆(XVI).

[0162] The reaction is suitably carried out in an aprotic solvent suchas dichloromethane and in the presence of a suitable reducing agent suchas sodium cyanoborohydride or sodium triacetoxyborohydride.

[0163] Compounds of formula (I) or compounds of formulas (II), (IV),(IVa), (V) or (VI) wherein R_(1a) is XR₆, wherein X is(CH2)_(r)N(R₅)C(O)(CH2)_(q), may be obtained from compounds of formula(I) wherein X is (CH₂)_(r)NHR₅ wherein r is an integer from 2 to 4 and qis an integer from 6 to 9, with the acid (XVII), HOC═O(CH₂)_(q)R₆ (XVII)and in the resence of an activating agent such as acyl halide.

[0164] The reaction is preferably carried out in a suitable aproticsolvent such as a halohydrocarbon (e.g. dichloromethane) orN,N-dimethylformamide optionally in the presence of a tertiary base suchas pyridine, dimethylaminopyridine or triethylamine and at a temperaturewithin the range of 0° to 120° C.

[0165] A suitable activating agent of the carboxyl group is for exampleacyl halide.

[0166] The hydroxyl protecting groups may be removed by well knownstandard procedures such as those described in T. W. Greene and P. G. MWuts in Protective Groups in Organic Synthesis 2^(nd) ed., John Wiley &Son,Inc. 1991. For example when R_(2a) is a trialkyllsilyl group, thismay be removed by treatment with tetrabutylammonium fluoride and aceticacid or by reaction with fluoride ions source such as triethyl aminetris (hydrogen fluoride) or this process is conveniently carried out ina solvent such as tetrahydrofuran or acetonitrile. Similarly, whenR_(2a) is alkanoyl (i.e. acetyl or benzoyl) these may be removed bytreatment with an alcohol (e.g. methanol or ethanol).

[0167] Compounds of formula (II) may be prepared by cyclisation of amalonic ester of formula (XVIII), wherein R_(1a) has the meaning definedin formula (II)

[0168] in the presence of a strong base such as 1,8 diazabicyclo[5.4.0]undec-7-ene. This reaction is conveniently carried out in anorganic solvent such acetonitrile, N,N dimethylformamide and the like.

[0169] Compounds of formula (XVIII) may be prepared by a reaction of acompounds of formula (XIX), wherein R_(1a) has the meaning defined informula (II), with a chloride of formula (XX) ClCOCH2COOMe(XX), in thepresence of a tertiary base such as pyridine, dimethylaminopyridine ortriethylamine and at a temperature within the range of 0° to 30°.

[0170] Compounds of formula (IV) may be prepared by a reaction of acompounds of formula (XIX) with a suitable activated derivative of theacid HOCOCH₂Cl(XXI).

[0171] Thus for example the esterification may be carried out byreaction with anhydride (ClCH₂CO)₂O (XXII) in a suitable aprotic solventsuch as a halohydrocarbon (e.g. dichloromethane) orN,N-dimethylformamide and in the presence of a tertiary base such aspyridine, dimethylaminopyridine or triethylamine and at a temperaturewithin the range of 0° C. to 120° C.

[0172] Compounds of formula (VII) may be prepared by treating a compoundof formula (IV) with sodium azide, subjecting the resulting azidocompound to the following operations: a) reduction by conventional meansfor reducing azido group to amino group and b) conversion of the groupNH₂ into the nitrogen protecting group N═R₁₂ wherein R₁₂ has the meaningdefined above and if required by removal of the hydroxy protecting groupR₂.

[0173] Compounds of formula (XIX), may be prepared by reacting11,12-carbonate, erythromycin A derivatives (XXIII), wherein R_(2a) is asuitable hydroxy protecting group, R₁₀ and R₁₁ have the meaning definedin formula (II) wherein R_(1a) has the meaning defined in formula (II),with a strong base such as 1,8 diazabicyclo [5.4.0]undec-7-ene.

[0174] The elimination reaction may be carried out in an organic solventsuch toluene, ethyl acetate, N,N dimethylformamide or a mixture thereof,conveniently with heating.

[0175] Compounds of formula (XXIII), may be prepared from erythromycin Aderivatives of formula (XXIV), wherein R_(1a) has the meaning defined informula (II),

[0176] by conversion of the 2′-hydroxy group into the correspondinghydroxy protected group and by conversion of the 11,12 hydroxy into acarbonate group using triphosgene in a suitable solvent such asdicholorometane, in the presence of pyridine.

[0177] Compounds of formula (XXIV), wherein R_(1a) is X or XR₆ in whichX is an optionally substituted C₁₋₁₀ alkylene, an optionally substitutedC₃₋₁₀ alkenylene or an optionally substituted C₃₋₁₀ alkynylene, may beprepared by alkylation of an oxime of formula (XXV)

[0178] wherein, R₁₃ is an oxime protecting group and R₂ and R_(2a) is ahydroxyl protecting group, with a compound of formula (XXVI) L-R_(1a)(XXVI) in which L is a suitable leaving group such as a halogen (e.g.chlorine, bromine or iodine) or a sulfonyl (e.g. tosyl,methanesulfonyl), in the presence of a base, followed by hydrolysis ofcladinose derivative and conversion of the 3-hydroxy group into the3-oxo.

[0179] The reaction with compound (XXV) is preferably carried out in asolvent such as a halohydrocarbon (e.g. dichloromethane), an ether (e.g.tetrahydrofuran, dimethoxyethane), acetonitrile and the like.

[0180] Examples of the bases which may be used include potassiumhydroxide, cesium hydroxide, tetraalkylammonium hydroxyde, sodiumhydride, potassium hydride and the like, followed by subsequent removalof oxime protecting group.

[0181] A suitable oxime protecting group is R₁₃, for example,1-isopropoxycyclohex-1-yl.

[0182] Oxime compounds (XXV) may be prepared by reaction of a compoundof formula (XXVI) wherein R₂ and R_(2a) is hydrogen using analogousmethods to those described in U.S. Pat. No. 6,110,965.

[0183] Compounds of formula (I) wherein R₃ is halogen may be preparedfrom compounds of formula (I) in which R₃ is hydrogen and R₂ is hydroxyprotecting group by reaction with a halogenating agent in the presenceof an organic or inorganic base.

[0184] Suitable halogenating agents include N-fluoro benzensulfonimide,SELECTFLUOR™ for fluorination, pyridinium tribromide or cyanogen bromidefor bromination or hexachloroethane for chlorination.

[0185] A convenient base for the reaction is selected from sodiumhydride, potassium hydride, sodium carbonate, potassiumhexamethyldisilazide, lithium diisopropylamide or pyridine. The reactionis carried out in a solvent such as N,N dimethylformamide,tetrahydrofuran or N-methylpyrrolidone or a mixture thereof,conveniently at a temperature within the range −78° to 60° C.

[0186] Alternatively the halo group in position 2 of the macrolide ringmay be introduced in an earlier step of the synthesis of compounds offormula (I). Thus, for example, it may be introduced by treating acompound of formulas (II), (IV), (IVa), (V), (VII), (VIII), (X), (XI),(XII), (XIII), (XIV), (XV), (XVIII), (XIX), (XXIII) or (XXIV) providedthat R₁₀ together with R₁₁ is an oxygen atom, using the method abovedescribed for obtaining compounds of formula (I) wherein R₃ is a halogroup.

[0187] Compounds of formulas (VI), (VIa), (IX), (XVI), (XVII), (XX),(XXI) or (XXII) may be prepared using methods known in the art.

[0188] The nitrogen protection reaction may be carried out with anappropriate imine such as benzophenone imine in an aprotic solvent, e.g.dichloromethane, preferably at room temperature.

[0189] Where it is desired to isolate a compound formula (I) as a saltthereof, for example a pharmaceutically acceptable salt, this may beachieved by reacting the compound of formula (I) in the form of the freebase with an appropriate amount of suitable acid and in a suitablesolvent such as an alcohol (e.g. ethanol or methanol), an ester (e.g.ethyl acetate) or an ether (e.g. diethyl ether or tetrahydrofuran).

[0190] Pharmaceutically acceptable salts may also be prepared from othersalts, including other pharmaceutically acceptable salts, of thecompound of formula (I) using conventional methods.

[0191] Suitable hydroxy protecting reagent are those described by T. W.Greene and P. G. M Wuts in Protective Groups in Organic Synthesis 2^(nd)ed., John Wiley & Son, Inc 1991, which is incorporating by reference.Examples of suitable hydroxy protecting reagents include aceticanhydride, benzoic anhydride or a trialkylsilyl chloride in a proticsolvent. Examples of aprotic solvent are dichloromethane,NN-dimethylformamide, dimethylsulfoxide, tetrahydrofuran and the like.

[0192] The hydroxyl protecting groups may be removed by well knownstandard procedures. For example when R_(2a) is a trialkyllsilyl group,this may be removed by treatment with tetrabutylammonium fluoride andacetic acid or by reaction with fluoride ions source such as triethylamine tris (hydrogen fluoride) or this process is conveniently carriedout in a solvent such as tetrahydrofuran or acetonitrile. When R₂ orR_(2a) is alkanoyl (i.e acetyl or benzoyl) these may be removed bytreatment with an alcohol (e.g. methanol or ethanol).

[0193] The nitrogen protecting group may be removed by well knownstandard procedures such as those described in T. W. Greene and P. G. MWuts in Protective Groups in Organic Synthesis 2^(nd) ed., John Wiley&Son, Inc. 1991. Thus for example when R₈ and R₉ indipendently representalkoxycarbonyl group may be removed by acid hydrolisis.

[0194] In any of the formulae (I), (II), (IVa), (VIII), (X), (XI),(XII), (XIII), (XIV) or (XV) shown above when there is an asymmetriccarbon atom and no specific configuration is shown then the formulaincludes all possible configurations.

[0195] Specific stereoisomers of the compounds of formula (I) as definedin formula 1a and 1b essentially free of the other stereoisomers may beprepared using general processes described above starting with theappropriate stereisomer of formula (IV).

[0196] The process described above for preparing the compounds offormula (I) will in general give a mixture of diastereoisomers 1a and1b.

[0197] The individual stereoisomers of the compounds of formula (I) maybe separated each other by conventional techniques such as fractionalcrystallisation or more particularly by column chromatography, using forexample a silica column.

[0198] In a preferred embodiment of the invention the individualstereoisomer of formula (1a) wherein R is NH₂ may be prepared byepimerisation reaction of a compound of formula(1b) or mixture of (1a)and (1b) wherein R is NH₂. The reaction is carried out in the presenceof benzaldehyde and DBU, followed by hydrolysis of the imine derivativewith inorganic acid such as hydrochloride. The reaction is suitablecarried out in aprotic solvent such as for example toluene, N-Ndimethylformamide.

[0199] The assignment of the R or S configuration at the 21-positionhave been made according to the rules of Cahn, Ingold and Prelog,Experientia 1956, 12, 81.

[0200] When examples are obtained as a diastereoisomeric mixture of 21Rand 21S, unless otherwise stated, the ¹H-NMR spectra refers to the¹H-NMR spectra of the predominant diastereoisomer (i.e. 21 S).

[0201] The invention is further illustrated by the followingIntermediates and Examples which are not intended as a limitation of theinvention.

[0202] In the Intermediates and Examples unless otherwise stated:

[0203] Proton Magnetic Resonance (¹H-NMR) spectra were recorded at 500Mz, chemical shifts are reported in ppm downfield (δ) from Me₄Si, usedas internal standard, and are assigned as singlets (s), doublets (d),doublets of doublets (dd), triplets (t), quartets (q) or multiplets (m).

[0204] Mass spectra were acquired with a Hewlett Packard 1100 MSD MassSpectometer in positive electrospray ionisation.

[0205] Column chromathography was carried out over silica gel 60(230-400 mesh ASTM—Merck AG Darmstaadt, Germany). The TLC (Thyn LayerChromatography) monitoring was performed using Merck 60 F₂₅₄ as TLCplate.

[0206] Abbreviations which have been used in the description of thesynthetic methods that follow are: DBU1,8-diazabicyclo[5.4.0]undec-7-ene, DCM for dichloromethane, DIPEA forN,N-diisopropylethylamine, DMAP for 4-dimethylaminopyridine, DMF forN,N-dimethylformamide, DMSO for methyl sulfoxide, EDC for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, Et₂O fordiethyl ether, EtOAc for ethyl acetate, HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, MeOH for methanol, TEA for triethylamine and THFfor tetrahydrofuran, wt for weight.

Intermediate 1 2′,4″-O-Diacetyl-6-O-allyl-erythromycin A

[0207] To a solution of 6-OAllyl erythromycin A (1 g) in anhydrous DCM(5 mL) cooled to 0° C. TEA (0.5 mL), DMAP (0.008 g) and acetic anhydride(0.31 mL) were added under nitrogen atmosphere. The resulting mixturewas stirred at 0° C. for 1 h and overnight at room temperature. Then themixture was diluted with a saturated NH₄Cl aqueous solution (30 mL) andextracted with DCM (2×50 mL). The aqueous phase was neutralised with asaturated NaHCO₃ aqueous solution and extracted again with DCM (2×50mL). The combined organic layers were dried over Na₂SO₄ and evaporatedunder reduced pressure to give the title compound (1 g) as white foam.

[0208] m\z ([MH]⁺)=858.

Intermediate 211,12-Carbonate-2′,4″-O-diacetyl-11,12-dideoxy-6-O-allyl-erythromycin A

[0209] To a solution of intermediate 1 (4.13 g) in anhydrous DCM (85 mL)cooled to 0° C., pyridine (0.8 mL) and then phosgene (20% sol intoluene, 2.55 mL) were added under nitrogen atmosphere. The resultingmixture was stirred at 0° C. for 30 min and then at room temperature for1 h. The reaction mixture was then diluted with water (150 mL) andextracted with DCM (2×200 mL). The organic layer was washed with water(3×100 mL), dried over Na₂SO₄ and evaporated under reduced pressure togive the title compound (4.02 g).

[0210] m\z ([MH]⁺)=884.

Intermediate 311-Deoxy-2′,4″-O-diacetyl-10,11-didehydro-6-O-allyl-erythromycin A

[0211] To a solution of intermediate 2 (4.02 g) in toluene (45 mL) andEtOAc (23 mL), DBU (0.71 mL) was added at room temperature. Theresulting mixture was stirred at 85° C. for 6 h. The mixture was thendiluted with brine (100 mL), extracted with EtOAc (2×200 mL) and driedover Na₂SO₄. Solvent evaporation under reduced pressure and purificationby flash chromatography (eluting with: DCM/MeOH/NH₄OH 95/4/0.01) gavethe title compound (1.70 g).

[0212] m\z ([MH]⁺)=840.

Intermediate 412-Chloroethanoyl-11-deoxy-2′,4″-O-diacetyl-10,11-didehydro6-O-allyl-erythrmycin A

[0213] To a solution of intermediate 3 (1.7 g) in anhydrous DCM (50 mL)cooled to 0° C., pyridine (0.66 mL), DMAP (0.012 g) and chloroaceticanhydride (0.695 g) were added under nitrogen atmosphere. The resultingmixture was stirred for 30 min at 0° C. and then at room temperature for2.5 h. The mixture was diluted with water (50 mL), neutralised with asaturated NaHCO₃ aqueous solution and extracted with DCM (2×100 mL). Theorganic phase was washed with water (3×50 mL), dried over Na₂SO₄ andevaporated under reduced pressure to give the title compound (1.8 g).

[0214] m\z ([MH]⁺)=916.

Intermediate 52′-O-Acetyl-12-chloroethanoyl-3-decladinosyl-11-deoxy-10,11-didehydro-6-O-allyl-erythromycinA

[0215] To a solution of intermediate 4 (1.8 g) in THF (35 mL), a 6N HClaqueous solution (10 mL) was added at 0° C. The resulting mixture wasstirred overnight at room temperature and then was diluted with water(50 mL). The pH of the solution was brought to 8-9 by addition of solidNaHCO₃ and 1% NaOH aqueous solution and then the aqueous phase wasextracted with DCM (2×100 mL). Solvent evaporation under reducedpressure and treatment of the crude material with Et₂O gave the titlecompound (1.4 g).

[0216] m\z([MH]⁺)=716.

Intermediate 6(11S,21R)-2′-O-Acetyl-3-decladinosyl-11,12-dideoxy-6-O-allyl-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA

[0217] To a solution of intermediate 5 (1.3 g) in anhydrous DMF (40 mL)potassium cyanide (0.500 g) was added under nitrogen atmosphere. Thereaction mixture was stirred at room temperature for 1 h, quenched witha 5% NaHCO₃ aqueous solution (50 mL) and extracted with DCM (2×50 mL).Purification of the crude material by flash chromatography (elutingwith: DCM/MeOH/NH₄)H 95/4/0.01) gave the title compound (0.42 g).

[0218] m\z ([MH]⁺)=707.

Intermediate 72′-O-Acetyl-11,12-carbonate-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-erythromycinA

[0219] To a solution of2′-O-acetyl-3-decladinosyl-6-O-methyl-3-oxo-erythromycin A (0.500 g) inanhydrous DCM (20 mL) pyridine (1.5 mL) and phosgene (20% sol. intoluene, 1 mL) were sequentially added under nitrogen atmosphere. Thereaction mixture was stirred overnight at room temperature, thenquenched with a saturated NaHCO₃ aqueous solution (50 mL) and washedwith water (50 mL). The organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. Purification of the crude materialby flash chromatography (eluting with: DCM/MeOH 9/1) gave the titlecompound (0.360 g).

[0220] TLC: DCM/MeOH 9/1 (Rf=0.6).

Intermediate 82′-O-Acetyl-3-decladinosyl-11-deoxy-10,11-didehydro-6-O-methyl-3-oxo-erythromycinA

[0221] To a solution of intermediate 7 (0.210 g) in 2/1 mixture ofEtOAc/toluene (6 mL) DBU (0.05 mL) was added and the mixture was heatedto 85° C. for 6 h. The solution was allowed to reach room temperatureand the solvent evaporated under reduced pressure. Purification of thecrude material by flash chromatography (eluting with: DCM/MeOH 9/1) gavethe title compound (0.150 g).

[0222] TLC: DCM/MeOH 9/1 (Rf=0.7).

Intermediate 92′-O-Acetyl-12-chloroethanoyl-3-decladinosyl-11-deoxy-10,11-didehydro-6-O-methyl-3-oxo-erythromycinA

[0223] To a solution of intermediate 8 (0.150 g) in anhydrous DCM (3 mL)cooled at 0° C., pyridine (0.05 mL), chloroacetic anhydride (0.065 g)and DMAP (5 mg) were sequentially added under nitrogen atmosphere. Thereaction mixture was stirred for 4 h then quenched with water (10 mL)and extracted with DCM (2×10 mL). The organic phase was dried overNa₂SO₄, concentrated under reduced pressure and purified by flashchromatography (eluting with: DCM/MeOH 8/2) to give the title compound(0.060 g).

[0224] TLC: DCM/MeOH 9/1 (Rf=0.8).

Intermediate 10 2′,4″-O-Diacetyl-6-O-methyl-erythromycin A

[0225] To a solution of 6-O-methyl-erythromycin A (50 g) in anhydrousDCM (240 mL) cooled to 0° C., TEA (26.1 mL), DMAP (0.392 g) and aceticanhydride (15.2 mL) were added under nitrogen atmosphere. The resultingmixture was stirred at 0° C. for 45 min and overnight at roomtemperature. The mixture was then diluted with a NH₄Cl saturated aqueoussolution (200 mL) and extracted with DCM (2×200 mL). The aqueous phasewas neutralised with a saturated NaHCO₃ aqueous solution and extractedagain with DCM (2×200 mL). The combined organic layers were dried overNa₂SO₄ and evaporated under reduced pressure to give the title compound(50.7 g).

[0226] m\z([MH]⁺)=832.

Intermediate 1111,12-Carbonate-2′,4″-O-diacetyl-11,12-dideoxy-6-O-methyl-erythromycin A

[0227] To a solution of intermediate 10 (25.4 g) in anhydrous DCM (200mL) cooled to 0° C., pyridine (15 mL) and a solution of triphosgene (9g) in anhydrous DCM (50 mL) were added under nitrogen atmosphere. Theresulting mixture was stirred at 0° C. for 30 min and then at roomtemperature overnight. The mixture was then diluted with water (200 mL)and extracted with DCM (2×300 mL). The organic layer was washed withwater 3×100 mL), dried over Na₂SO₄ and evaporated under reduced pressureto give the title compound (25.5 g).

[0228] m\z ([MH]⁺)=858.

Intermediate 1211-Deoxy-2′,4″-O-diacetyl-10,11-didehydro-6-O-methyl-erythromycin A

[0229] To a solution of intermediate 11 (50.5 g) in 2/1 mixture oftoluene/EtOAc (675 mL), DBU (9.24 mL) was added at room temperature. Theresulting mixture was heated to 85° C. for 8 h and at room temperaturefor 5 h. The mixture was then diluted with brine (200 mL) and extractedwith EtOAc (3×200 mL). The organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. Crystallisation from acetone/watergave the title compound (46 g).

[0230] m\z ([MH]⁺)=814.

Intermediate 1311-Deoxy-2′,4″-O-diacetyl-10,11-didehydro-12-methoxycarbonylethanoyl-6-O-methyl-erythromycinA

[0231] To a solution of intermediate 12 (0.500 g) in anhydrous toluene(100 mL) and pyridine (0.250 mL) cooled to 0° C. methylmalonyl chloride(0.158 mL) was added. The temperature was allowed to reach roomtemperature and after stirring 1 hr, water (50 mL) was added. Theorganic layer was washed with brine (50 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. Purification of the crude materialby quick filtration through a filter of silica gel gave the titlecompound (0.560 g).

[0232] m\z ([MH]⁺)=914.

Intermediate 14 240-O-Acetyl-3-decladinosyl-11-deoxy-10,11-didehydro-12-metboxycarbonylethanoyl-6-O-methyl-erythromycinA

[0233] and

Intermediate 152′-O-Acetyl-3-decladinosyl-11-deoxy-10,11-didehydro-12-carboxyethanoyl-6-O-methyl-erythromycinA

[0234] Intermediate 13 (0.500 g) was stirred in a 2N HCl aqueoussolution (50 mL) and THF (1 mL) at room temperature for 6 h. Then themixture was cooled to 0° C. and a saturated K₂CO₃ aqueous solution wasadded until pH=9 was obtained. The aqueous phase was extracted with DCM(2×50 mL), the organic phase was washed with brine (50 mL), dried overNa₂SO₄ and concentrated under reduced pressure. The crude material waspurified by flash chromatography (eluting with: DCM/MeOH=95/5) to givethe title compound 14 (0.180 g) and the title compound 15 (0.180 g).

[0235] m\z ([MH]⁺) (14)=714. m\z ([MH]⁺) (15)=680.

Intermediate 16(10R,S,11S,21R,S)-2′-O-Acetyl-3-decladinosyl-11,12-dideoxy-6-O-methyl-12,11-[oxycarbonyl-(methoxycarbonyl)-methylene]-erythromycinA

[0236] A solution of intermediate 14 (0.150 g) in water (1.5 mL),acetonitrile (13.5 mL) and DBU (0.050 mL) was stirred at 40° C. for 6 h.After evaporating the solvent under reduced pressure, the residue wasdissolved in DCM (20 mL) and washed with water (50 mL). The organicphase was dried over Na₂SO₄ and concentrated under reduced pressure. Thecrude material was purified by flash chromatography (eluting with:DCM/MeOH 95/5) to give the title compound (0.070) g.

[0237] m\z ([MH]⁺)=714.

Intermediate 17(10R,S,11R)2′-O-Acetyl-3-decladinosyl-11,12-dideoxy-6-O-methyl-12,11-[oxycarbonylmethylene]-erythromycinA

[0238] A stirred mixture of intermediate 16 (0.050 g) and lithiumchloride (6 mg) in DMF (1 mL) was refluxed for 4 h. The reaction mixturewas allowed to reach room temperature, then poured into an iced solutionof a 3% NaHCO₃ aqueous solution and the aqueous phase extracted with DCM(2×15 mL). The organic phase was washed with water (2×10 mL), dried overNa₂SO₄ and concentrated under reduced pressure. The crude material waspurified by flash chromatography (DCM/MeOH: 95/5) to give the titlecompound (0.010 g)

[0239] m\z ([MH]⁺)=656.

Intermediate 182′-O-Acetyl-12-azidoethanoyl-3-decladinosyl-11-deoxy-10,11-didehydro-6-O-allyl-erythromycinA

[0240] To a solution of intermediate 5 (1.42 g) in anhydrous DMF (110mL), sodium azide (0.211 g) was added under nitrogen atmosphere. Themixture was heated to 80° C. for 10 min then quenched with water (100mL) and extracted with EtOAc (3×200 mL). The organic layer was driedover Na₂SO₄ and concentrated under vacuum to give the title compound(1.36 g).

[0241] m\z ([MH]⁺)=723.

Intermediate 192′-O-Acetyl-12-aminoethanoyl-3-decladinosyl-11-deoy-10,11-didehydro-6-O-allyl-erythromycinA

[0242] To a solution of intermediate 18 (1.36 g) in THF (25 mL),triphenylphosphine (0.985 g) and water (0.034 mL) were added. Themixture was stirred at room temperature overnight. After evaporating thesolvent, the crude material was dissolved in DCM (100 mL) and washedwith water (2×100). The organic layer was dried over Na₂SO₄ andconcentrated under vacuum to give the title compound (1.3 g).

[0243] m\z ([MH]⁺)=697.

[0244] Intermediate 20

2′-O-Acetyl-12-(benzhydrylidene)-aminoethanoyl-3-decladinosyl-11-deoxy-10,11-didehydro-6-O-allyl-erythromycinA

[0245] A solution of intermediate 19 (1.3 g) and benzophenone imine (0.9mL) in anhydrous DCM (15 mL) was stirred at room temperature. After 30 hthe reaction was quenched with water (50 mL) and extracted with DCM(3×100 mL). The organic layer was dried over Na ₂SO₄ and concentratedunder vacuum to give the title compound (1.6 g).

[0246] m\z ([MH]⁺)=861.

Intermediate 21(11S,21R,S)-2′-O-Acetyl-3-decladinosyl-11,12-dideoxy-6-O-allyl-12,11-[oxycarbonyl-(benzhydrylideneamino)-methylene]-erythromycinA

[0247] A solution of intermediate 20 (1.6 g) and DBU (0.3 mL) inacetonitrile (90 mL) and water (9 mL) was stirred at room temperature.After evaporating the solvent, the crude material was dissolved in DCM(100 mL). The organic phase was washed with water (2×100 mL), dried overNa₂SO₄ and concentrated under vacuum. The crude material was purified byflash chromatography (eluting with: DCM/MeOH/NH₃ 9.5/0.4/0.03) to givethe title compound (0.528 g).

[0248] m\z ([MH]⁺)=861.

Intermediate 22(11S,21R,S)-2′-O-Acetyl-3-decladinosyl-11,12-dideoxy-6-O-allyl-3-oxo-12,11-[oxycarbonyl-(benzhydrylideneamino)-methylene]-erythromycinA

[0249] To a solution of intermediate 21 (0.528 g) and EDC (0.70 g) inDCM anhydrous (40 mL) cooled to 0° C., DMSO (0.8 mL) was added undernitrogen atmosphere. After 10 min at 0° C., a solution of pyridiniumtrifluoroacetate (0.72 g) in DCM (2 mL) was slowly added. After 10 minthe ice bath was removed and the mixture stirred for 1 h. The reactionmixture was quenched with water (50 mL) and extracted with DCM (3×100mL). The organic layer was dried over Na₂SO₄ and concentrated undervacuum to give the title compound (0.520 g).

[0250] TLC: DCM/MeOH/NH₃ 20/2/0.2 (Rf=39).

Intermediate 2312-Chloroethanoyl-11-deoxy-2′,4″-O-diacetyl-10,11-didehydro-6-O-methyl-erythromycinA

[0251] To a solution of intermediate 12 (20 g) in anhydrous DCM (340 mL)cooled to 0° C., pyridine (6 mL) and chloroacetic anhydride (8.4 g) wereadded under nitrogen atmosphere and the reaction was allowed to reachroom temperature. After 18 h the reaction was quenched with water (300mL), the organic phase washed with a saturated NH₄Cl aqueous solution(150 mL) and brine (150 mL), the aqueous phase extracted again with DCM(2×300 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. Crystallisation of the crudematerial from acetone/water gave the title compound (20.4 g).

[0252] m\z ([MH]⁺)=890.

Intermediate 242′-O-Acetyl-12-chloroethanoyl-3-decladinosyl-11-deoxy-10,11-didehydro-6-O-methyl-erythromycinA

[0253] To a solution of intermediate 23 (20.2 g) in THF (200 mL) cooledto 0° C. a 3N HCl aqueous solution (400 mL) was added dropwise. Then thereaction was allowed to reach room temperature and stirred overnight.The solution was neutralised with a saturated NaHCO₃ aqueous solutionand extracted with DCM (2×250 mL). The organic phase was dried overNa₂SO₄ and concentrated under reduced pressure. The crude material waspurified by quick filtration through a silica pad to give the titlecompound (15.4 g).

[0254] m\z ([MH]⁺)=690.

Intermediate 252′-O-Acetyl-12-azidoethanoyl-3-decladinosyl-11-deoxy-10,11-didehydro-6-O-methyl-erythromycinA

[0255] To a solution of intermediate 24 (4.2 g) in anhydrous DMF (170mL), sodium azide (0.600 g) was added under nitrogen atmosphere. Themixture was heated to 80° C. for 1 hr then quenched with water (150 mL)and extracted with EtOAc (3×300 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated under vacuum to give the titlecompound (4.2 g).

[0256] m\z ([MH]⁺)=697.

Intermediate 262′-O-Acetyl-12-aminoethanoyl-3-decladinosyl-11-deoxy-10,11-didehydro-6-O-methyl-erythromycinA

[0257] To a solution of intermediate 25 (4.2 g) in THF (75 mL),triphenylphosphine (1.6 g) was added. After stirring at room temperatureovernight water (3 mL) was added and the reaction mixture stirred for 6hr. After evaporating the solvent, the crude material was dissolved inDCM (400 mL) and washed with water (2×200). The organic layer was driedover Na₂SO₄ and concentrated under vacuum to give the title compound(4.0 g).

[0258] TLC: DCM/MeOH 10/1 (Rf=0.28).

Intermediate 272′-O-Acetyl-12-(benzhydrylidene)-aminoethanoyl-3-decladinosyl-11-deoxy-10,11-didehydro-6-O-methyl-erythromycinA

[0259] A solution of intermediate 26 (4.0 g) and benzophenone imine (2.6mL) in anhydrous DCM (40 mL) was stirred at room temperature. After 36 hthe reaction was quenched with water (100 mL) and extracted with DCM(3×300mL). The organic layer was dried over Na₂SO₄ and concentratedunder vacuum. The crude material was purified by flash chromatography(eluting with: DCM/MeOH 95/5) to give the title compound (3.5 g).

[0260] TLC: DCM/MeOH 10/1 (Rf=0.38).

Intermediate 28(11S,21R,S)-2′-O-Acetyl-3-decladinosyl-11,12-dideoxy-6-O-methyl-12,11-[oxycarbonyl-(benzhydrylideneamino)-methylene]-erythromycinA

[0261] A solution of intermediate 27 (3.0 g) and DBU (0.540 mL) inacetonitrile (135 mL) and water (15 mL) was stirred at room temperaturefor 3 h. After evaporating the solvent, the crude material was dissolvedin DCM (300 mL) and washed with water (100 mL). The organic layer wasdried over Na₂SO₄ and concentrated under vacuum to give the titlecompound (2.9 g).

[0262] TLC: DCM/MeOH 10/1 (Rf=0.38).

Intermediate 29(11S,21R,S)-2′-O-Acetyl-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(benzhydrylideneamino)-methylene]-erythromycinA

[0263] To a solution of intermediate 28 (1.5 g) and EDC (3.10 g) in DCM(100 mL) cooled to 0° C., DMSO (3.45 mL) was added. After 10 min. at 0°C., a solution of pyridinium trifluoroacetate (3.12 g) in DCM (15 mL)was slowly added under nitrogen atmosphere. After 10 min the ice bathwas removed. The reaction mixture was stirred for 3 h then quenched withwater (150 mL) and extracted with DCM (3×250 mL). The organic layer wasdried over Na₂SO₄ and concentrated under vacuum. The crude material waspurified by flash chromatography (eluting with: DCM/MeOH 95/5) to givethe title compound (1.2 g).

[0264]¹H-NMR (CDCl₃) δ: 7.8-7.2 (m, 10H), 6.40 (dd, 1H), 5.15 (s, 1H),4.73 (m, 1H), 4.42 (d, 1H), 4.16 (d, 1H), 3.90 (q, 1H), 3.55 (m, 1H),3.17 (m, 1H), 2.95 (m, 1H), 2.94 (d, 1H), 2.67 (m, 1H), 2.53 (s, —OCH₃),2.43 (m, 1H), 2.33 (s, N(CH₃)₂), 2.05 (s, 3H), 2.00 (m, 1H), 1.74 (m,1H), 1.65 (m, 1H), 1.53 (s, 3H), 1.38 (d, 3H), 1.23 (s, 3H), 1.29 (d,3H), 1.25 (m, 1H), 1.25 (d, 3H), 1.14 (d, 3H), 1.07 (d, 3H), 0.83 (t,3H). TLC: DCM/MeOH 10/1 (Rf=0.30).

Intermediate 30 Trifluoro-methanesulfonic acid quinolin-5-yl ester

[0265] To a suspension of quinolin-5-ol (0.300 g) in anhydrous DCM (12ml) cooled to −30° C. 2,6-dimethyl-pyridine (0.257 g), DMAP (0.050 g)and trifluoromethensulfonic anhidride (0.670 g) were sequentally added.The temperature was allowed to reach room temperature and the reactionmixture was stirred overnight. The mixture was poured into a saturatedNaHCO₃ aqueous solution (15 ml), extracted with EtOAc (3×15 ml). Theorganic phase was dried over Na₂SO₄ and concentrated under reducedpressure. The crude material was purified by flash chromatography(eluting with: cyclohexane/EtOAc from 7/3 to 6/4) to give the titlecompound (0.197 g).

[0266] m\z ([MH]⁺)=278.

Intermediate 31 Trifluoro-methanesulfonic acid quinolin-6-yl ester

[0267] To a suspension of quinolin-6-ol (0.500 g) in anhydrous DCM (20ml) cooled to −30° C. 2,6-dimethyl-pyridine (0.46 ml), DMAP (0.084 g)and trifluoromethensulfonic anhidride (0.67 ml) were sequentally added.The temperature was allowed to reach room temperature and the reactionmixture was stirred overnight. The mixture was diluted with a saturatedNaHCO₃ aqueous solution (35 ml), extracted with EtOAc (3×50 ml). Theorganic phase was washed with brine (50 ml), dried over Na₂SO₄ andconcentrated under reduced pressure. The crude material was purified byflash chromatography (eluting with: cyclohexane/EtOAc 8/2) to give thetitle compound (0.210 g).

[0268] TLC: cyclohexane/EtOAc 2/8 (Rf=0.70) m\z ([MH]⁺)=278.

Intermediate 32 Trifluoro-methanesulfonic acid quinolin-7-yl ester

[0269] To a solution of quinolin-7-ol (0.500 g) in anhydrous pyridine(2.5 ml) cooled to 0° C. trifluoromethensulfonic anhidride (0.64 ml) wasadded and the mixture stirred at 0° C. for 5 min. The temperature wasallowed to reach room temperature and the reaction mixture was stirredfor 3 h. The mixture was diluted with a 1M aqueous HCl solution (25 ml)and extracted with Et₂O (3×50 ml). The organic phase was washed withbrine (50 ml), dried over Na₂SO₄ and concentrated under reducedpressure. The crude material was purified by flash chromatography(eluting with: cyclohexane/EtOAc 3/7) to give the title compound (0.770g).

[0270] m\z ([MH]⁺)=278.

Intermediate 33(11S,21R)-2′-O-Acetyl-3-decladinosyl-11,12dideoxy-6-O-allyl-3-oxo-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA

[0271] To a solution of intermediate 6 (0.33 g) in DCM (30 mL)Dess-Martin periodinane (0.300 g) was added portionwise within 3 h. Asolution of Na₂S₂O₃ (5% in a saturated NaHCO₃ aqueous solution, 20 mL)was added and the mixture was stirred for 1 h. The aqueous phase wasextracted with DCM (2×50 mL), the organic phase washed with water (50mL), dried over Na₂SO₄ and concentrated under reduced pressure.Purification of the crude material by flash chromatography (elutingwith: DCM/MeOH/NH₃ 9.6/0.3/0.09) gave the title compound (0.13 g).

[0272]¹H-NMR (CDCl₃) δ: 5.69 (m, 1H), 5.43 (dd, 1H), 5.09 (m, 2H), 4.75(m, 1H), 4.73 (s, 1H), 4.47 (d, 1H), 4.39 (d, 1H), 3.91 (q, 1H), 3.70(m, 2H), 3.63 (m, 1H), 3.21 (m, 1H), 3.20 (s, 1H), 3.12 (m, 1H), 2.70(m, 1H), 2.65 (m, 1H), 2.26 (s, N(CH₃)₂), 2.04 (s, 3H), 1.94 (m, 1H),1.70 (m, 1H), 1.65 (m, 1H), 1.60 (s, 3H), 1.55 (m, 1H), 1.36 (d, 3H),1.33 (s, 3H), 1.26 (d, 6H), 1.13 (d, 3H), 1.06 (d, 3H), 0.93 (t, 3H).

Intermediate 34(11S,21R)-3-Decladinosyl-11,12-dideoxy-6-O-allyl-3-oxo-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA

[0273] A solution of intermediate 33 (0.005 g) in MeOH (0.5 mL) wasstirred at room temperature overnight. Solvent evaporation under reducedpressure gave the title compound (0.003 g).

[0274]¹H-NMR (CDCl₃) δ: 5.71 (m, 1H), 5.44 (dd, 1H), 5.08 (m, 2H), 4.72(s, 1H), 4.43 (d, 1H), 4.40 (d, 1H), 3.94 (q, 1H), 3.72 (m, 2H), 3.62(m, 1H), 3.20 (m, 4H), 2.68 (m, 1H), 2.52 (m, 1H), 2.29 (s, N(CH₃)₂),1.94 (m, 1H), 1.81 (m, 1H), 1.65 (m, 1H), 1.60 (m, 1H), 1.61 (s, 3H),1.42 (d, 3H), 1.35 (s, 3H), 1.34 (d, 3H), 1.26 (d, 3H), 1.12 (d, 3H),1.08 (d, 3H), 0.93 (t, 3H).

Intermediate 35(11S,21R)-2′-O-Acetyl-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA

[0275] To a solution of intermediate 9 (0.060 g) in anhydrous DMF (16mL) potassium cyanide (0.051 g) was added under nitrogen atmosphere. Thereaction mixture was stirred at room temperature for 2 h, quenched witha saturated NaHCO₃ aqueous solution (30 mL) and extracted with DCM (3×30mL). The organic phase was then washed with brine (30 mL), dried overNa₂SO₄ and evaporated under reduced pressure. Purification of the crudematerial by flash chromatography (eluting with: DCM/MeOH 95/5) gave thetitle compound (0.017 g).

[0276]¹H-NMR (CDCl₃) δ: 5.27(dd, 1H), 4.74 (dd, 1H), 4.62 (d, 1H), 4.42(d, 1H), 4.26 (d, 1H), 3.84 (q, 1H), 3.56 (m, 1H), 3.16 (m, 1H1),3.10-3.0 (m, 2H), 2.77 (s, —OCH₃), 2.68 (m, 1H), 2.60 (m, 1H), 2.25 (s,N(CH₃)₂), 2.05 (m, 3H), 1.90 (m, 1H), 1.68 (m, 1H), 1.63 (m, 2H), 1.56(s, 3H), 1.39 (d, 3H), 1.35 (m, 1H), 1.30 (s, 3H), 1.26 (d, 3H), 1.18(d, 3H), 1.14 (d, 3H), 1.06 (d, 3H), 0.92 (t, 3H). TLC: DCM/MeOH 95/5(Rf=0.57).

Intermediate 3611S,21R)-3-Decladinosyl-11,12dideoy-6-methyl-3-oxo-12,11-[oxycarbonyl-(cyano-methylene]-erythromycinA

[0277] A solution of intermediate 35 (0.024 g) in MeOH (1 mL) wasstirred at room temperature for 24 h. Solvent evaporation under reducedpressure gave the title compound (0.020 g).

[0278]¹H-NMR (CDCl₃) δ: 5.26 (dd, 1H), 4.61 (d, 1H), 4.34 (d, 1H), 4.28(m, 1H), 3.87 (q, 1H), 3.57 (m, 1H), 3.18 (m, 1H), 3.15 (t, 1H), 3.12(m, 1H), 3.06 (m, 1H), 2.78 (s, —OCH₃), 2.62 (m, 1H), 2.46 (m, 1H), 2.27(s, N(CH₃)₂), 1.91 (m, 1H), 1.84 (m, 1H), 1.70 (m, 1H), 1.68 (m, 1H),1.62 (m, 1H), 1.57 (s, 3H), 1.41 (d, 3H), 1.34 (d, 3H), 1.34 (s, 3H),1.24 (s, 1H), 1.26 (d, 3H), 1.14 (d, 3H), 1.07 (d, 3H), 0.92 (t, 3H).TLC: DCM/MeOH 9/1 (Rf=0.38).

Intermediate 37(10R,S,11R)-3-Decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonylmethylene]-erythromycinA

[0279] To a solution of intermediate 17 (0.050 g) in anhydrous DCM (25mL), EDC (0.102 g) and DMSO (0.115 mL) were added under nitrogenatmosphere. The mixture was cooled to 0° C. and a solution of pyridiniumtrifluoroacetate (0.102 g) in DCM (0.5 mL) was added dropwise. Themixture was allowed to reach room temperature, after stirring for 5 hwater (10 mL) was added and the mixture extracted with DCM (2×20 mL).The organic phase was dried over Na₂SO₄ and concentrated under reducedpressure The crude material was purified by preparative TLC (elutingwith: DCM/MeOH 95/5); the recovered silica gel was stirred 18 h in MeOHthen filtered. Solvent evaporation under reduced pressure gave the titlecompound (0.025 g).

[0280]¹H-NMR (CDCl₃) δ: 4.90 (dd, 1H), 4.32 (d, 1H), 4.24 (d, 1H), 3.85(q, 1H), 3.56 (m, 1H), 3.32 (d, 1H), 3.18 (m, 1H), 3,12 (m, 1H), 3.02(m, 1H), 2.80 (d, 1H), 2.71 (dd, 1H), 2.63 (s, —OCH₃), 2.55 (m, 1H),2.47 (m, 1H), 2.27 (s, N(CH₃)₂), 1.87 (m, 1H), 1.70 (m, 1H), 1.62 (m,1H), 1.58 (m, 1H), 1.50 (s, 3H), 1.38 (d, 3H), 1.30 (d, 3H), 1.31 (s,3H), 1.30 (m, 1H), 1.25 (d, 3H), 1.22 (m, 1H), 1.14 (d, 3H), 1.07 (d,3H), 0.86 (t, 3H).

Intermediate 38(11S,21R,S)-2′-acetoxy-3-decladinosyl-11,12-dideoxy-6-O-allyl-3-oxo-12,11-[oxycarbonyl-(amino)-methylene]-erythromycinA

[0281] A solution of intermediate 22 (0.52 g) in acetonitrile (66 mL)and a 1.2N HCl aqueous solution (154 mL) was stirred at room temperaturefor 1 h. After neutralising the mixture with solid Na₂CO₃ andevaporating the solvent under vacuum, the mixture was extracted with DCM(2×100 mL). The organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure to give of the title compound (0.47 g).

[0282]¹H-NMR (CDCl₃) δ: 5.88 (dd, 1H), 5.70 (m, 1H), 5.13 (d, 1H), 4.75(m, 1H), 4.57 (s, 1H), 4.44 (d, 1H), 4.38 (d, 1H), 3.91 (q, 1H), 3.75(q, dd), 3.61 (m, 1H), 3.50 (m, 1H), 3.24 (m, 1H), 3.08 (m, 1H), 2.70(m, 1H), 2.64 (m, 1H), 2.46 (bs, 1H), 2.26 (s, N(CH₃)₂), 2.18 (m, 6H),1.60-1.4 (m, 5H), 1.40−1.2 (m, 13H), 1.15 (d, 3H), 1.08 (d, 3H), 0.88(t, 3H).

Intermediate 39(11S,21R,S)-3-Decladinosyl-11,12-dideoxy-6-O-allyl-3-oxo-12,11-[oxycarbonyl-(amino)-methylene]-erythromycinA

[0283] A solution of intermediate 38 (0.002 g) in MeOH (0.3 mL) wasstirred at room temperature overnight. Solvent evaporation under reducedpressure gave the title compound (0.002 g).

[0284]¹H-NMR (CDCl₃) δ: 5.82 (dd, 1H), 5.73 (m, 1H), 5.14 (d, 1H), 5.02(d, 1H), 4.54 (s, 1H), 4.40 (d, 1H), 4.38 (d, 1H), 3.93 (q, 1H), 3.76(m, 1H), 3.62 (m, 1H), 3.52 (m, 1H), 3.24 (m, 1H), 3.21 (m, 1H), 3.09(m, 1H), 2.66 (m, 1H), 2.50 (m, 1H), 2.47 (m, 1H), 2.28 (s, N(CH₃)₂),1.95 (m, 1H), 1.85 (m, 2H), 1.80-0.80 (several m, 27H). m\z ([MH]⁺)=653.

Intermediate 40(11S,21R,S)-2′-O-Acetyl-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(amino)-methylene]-erythromycinA

[0285] A solution of intermediate 29 (1.1 g) in acetonitrile (30 mL) anda 1.2N HCl aqueous solution (70 mL) was stirred at room temperature for1 h. After neutralising the mixture with solid Na₂CO₃ and evaporatingthe solvent, the mixture was extracted with DCM (3×200 mL). The organiclayer was dried over Na₂SO₄ and concentrated under vacuum to give thetitle compound (0.9 g).

[0286]¹H-NMR (CDCl₃) δ: 5.45 (dd, 1H), 4.75 (m, 1H), 4.45 (d, 1H), 4.40(d, 1H), 4.21 (d, 1H), 3.82 (q, 1H), 3.54 (m, 1H), 3.09 (m, 1H), 2.69(m, 1H), 2.68 (s, —OCH₃), 2.58 (m, 1H), 2.41(m, 1H), 2.25 (s, N(CH₃)₂),2.07 (m, 3H), 1.95 (m, 1H), 1.75 (m, 1H), 1.60 (m, 1H), 1.49 (s, 3H),1.39 (d, 3H), 1.35 (m, 1H), 1.31 (s, 3H), 1.26 (d, 3H), 1.17 (d+d, 6H),1.09 (d, 3H), 0.88 (t, 3H). TLC: DCM/MeOH 10/1 (Rf=0.48).

Intermediate 41(11S,21R,S)-3-Decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(amino)-methylene]-erythromycinA

[0287] A solution of intermediate 40 (0.012 g) in MeOH (1 mL) wasstirred at room temperature overnight. After evaporating the solvent,the crude material was purified by flash chromatography (eluting with:DCM/MeOH 100:5) to give the title compound (0.007 g).

[0288]¹H-NMR (CDCl₃) δ: 5.41 (dd, 1H), 4.42 (d, 1H), 4.33 (d, 1H), 4.22(d, 1H),3.83 (q, 1H), 3.56 (m, 1H), 3.23 (d, 1H), 3.12 (m, 1H), 3.02 (m,1H), 2.80 (d, 1H), 2.69 (s, —OCH₃), 2.60 (m, 1H), 2.54 (m, 1H), 2.40 (d,1H), 2.33 (s, N(CH₃)₂), 1.95 (m, 3H), 1.9-1.50 (m, 3H), 1.49 (s, 3H),1.39 (d, 3H), 1.35 (m, 1H), 1.33 (s, 3H), 1.32 (m, 1H), 1.31 (d, 3H),1.26 (d, 3H), 1.16 (d, 3H), 1.10 (d, 3H), 0.88 (t, 3H).

EXAMPLE 1(11S,21R)2′-O-Acetyl-3-decladinosyl-11,12-dideoxy-6-O-[(quinolin-3-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA

[0289] A mixture of intermediate 33 0.065 g), palladium (II) acetate(0.004 g) and tri-o-tolylphosphine (0.011 g) in anhydrous DMF (2 mL) wasflushed with nitrogen. To this solution 3-bromoquinoline (0.025 mL) andTEA (0.0026 mL) were added. The reaction mixture was heated at 50° C.for 30 min and stirred at 90° C. for 19 h. The reaction mixture wasdiluted with EtOAc (10 mL), washed with a 5% NaHCO₃ aqueous solution (10mL) and brine (10 mL). The organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. Purification of the crude materialby flash chromatography (eluting with: DCM/MeOH/NH₃ 9.6/0.3/0.09) gavethe title compound (0.010 g).

[0290]¹H-NMR (CDCl₃) δ: 8.99 (d, 1H), 8.14 (d, 1H), 8.08 (d, 1H), 7.85(d, 1H), 7.66 (m, 1H), 7.53 (m, 1H), 6.58 (d, 1H), 6.27 (m, 1H), 5.47(dd, 1H), 4.77 (d, 1H), 4.78 (m, 1H), 4.28 (d, 1H), 3.99 (m, 2H), 3.95(q, 1H), 3.50 (m, 1H), 3.29 (s, 1H), 3.28 (m, 1H), 3.14 (m, 1H), 2.67(m, 2H), 2.28 (s, N(CH₃)₂), 2.09 (s, 3H), 1.97 (m, 1H), 1.77-1.70 (m,3H), 1.69 (m, 1H), 1.62 (s, 3H), 1.42 (s, 3H), 1.38 (d, 3H), 1.30 (m,1H), 1.29 (d, 3H), 1.17 (d, 3H), 1.08 (d, 3H), 1.04 (d, 3H), 0.95 (t,3H).

EXAMPLE 2(11S,21R)-3-Decladinosyl-11,12-dideoxy-6-O-[(quinolin-3-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-(cyano)methylene]-erythromycinA

[0291] A solution of example 1 (0.010 g) in MeOH (1 mL) was stirred atroom temperature overnight. Solvent evaporation under reduced pressuregave the title compound (0.007 g).

[0292]¹H-NMR (CDCl₃) δ: 9.00 (d, 1H), 8.15 (d, 1H), 8.07 (d, 1H), 7.84(d, 1H), 7.65 (t, 1H), 7.52 (t, 1H), 6.58 (m, 1H), 6.29 (m, 1H), 5.45(dd, 1H), 4.76 (d, 1H), 4.45 (d, 1H), 4.39 (d, 1H), 3.99 (m, 3H), 3.51(m, 1H), 3.28 (s, 1H), 3.26 (m, 1H), 3.16 (m, 1H), 2.70 (m, 2H), 2.36(m, 1H), 2.36 (s, N(CH₃)₂), 1.95 (m, 1H), 1.90-1.50 (m+s, 4H+3H),1.43(s, 3H), 1.42 (d, 3H), 1.38 (s, 3H), 1.30 (m, 1H), 1.16 (d, 3H),1.09 (d+d, 3H+3H), 0.94 (t, 3H).

EXAMPLE 3(11S)-3-Decladinosyl-11,12-dideoxy-6-O-[(quinolin-3-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-methylene]-erythromycinA

[0293] A suspension of example 1 (0.020 g) and neutral activatedaluminum oxide (0.030 g) in a mixture of THF/water 97/3 (3 mL) washeated under reflux for 4 days. The mixture was filtered and the solidresidue washed with AcOEt (3×2 mL). The filtrate was dried over Na₂SO₄and evaporated under reduced pressure. The crude material was dissolvedin MeOH (1 mL) and stirred overnight. After evaporating the solvent,purification by flash chromatography (eluting with: DCM/MeOH 95:5)afforded the title compound (0.014 g).

[0294]¹H-NMR (CDCl₃) δ: 9.05 (d, 1H), 8.16 (d, 1H), 8.07 (d, 1H), 7.83(d, 1H), 7.66 (t, 1H), 7.53 (t, 1H), 6.53 (d, 1H), 6.20 (m, 1H), 4.82(dd, 1H), 4.44 (d, 1H), 4.38 (d, 1H), 4.00 (q, 1H), 3.86-3.68 (m, 2H),3.60 (m, 1H), 3.28 (s, 1H), 3.19 (m, 1H), 3.15 (m, 1H), 3.10 (m, 1H),2.84 (m, 1H), 2.64 (m, 1H), 2.44 (m, 1H), 2.38 (dd, 1H), 2.27 (s,N(CH₃)₂), 1.90-1.80 (m, 2H), 1.70 (m, 1H), 1.68 (m, 1H), 1.60 (m, 1H),1.44 (s, 3H), 1.45 (d, 3H), 1.40 (d, 3H), 1.26 (s, 3H), 1.25 (m, 1H),1.22 (d, 3H), 1.16 (d, 3H), 1.04 (d, 3H), 0.83 (t, 3H).

EXAMPLE 4(11S,21R)3-Decladinosyl-11,12-dideoxy-6-O-[(quinolin-5-yl)-propen-3-yl]-3oxo-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA

[0295] A mixture of intermediate 33 (0.150 g), palladium (II) acetate(0.019 g) and tri-o-tolylphosphine (0.051 g) in anhydrous DMF (2 mL) wasflushed with nitrogen. To this solution TEA (0.120 mL) and intermediate30 (0.233 g) were added. The reaction mixture was stirred at 90° C. for48 h. The reaction mixture was diluted with EtOAc (10 mL), the organicphase washed with a 5% NaHCO₃ aqueous solution (5 mL) and brine (5 mL),dried over Na₂SO₄ and concentrated under reduced pressure. Thepurification of the crude material by flash chromatography (elutingwith: DCM/MeOH from 100/0 to 96/4) gave a compound that was dissolved inMeOH (3 mL) and stirred overnight at room temperature. After evaporationof the solvent, the crude material was purified by flash chromatography(eluting with: DCM/MeOH 94/6) affording the title compound (0.010 g).

[0296]¹H-NMR (CDCl₃) δ: 8.91 (m, 1H), 8.51 (d, 1H), 8.02 (d, 1H), 7.76(d, 1H), 7.72 (t, 1H), 7.42 (m, 1H), 7.11 (d, 1H), 6.16 (m, 1H), 4.77(d, 1H), 4.04 (d, 2H), 3.31 (m, 1H), 2.72 (m, 1H), 1.86 (m, 1H), 1.75(m, 1H), 1.63 (s, 3H), 1.47 (s, 3H).

EXAMPLE 5(11S,21R)-3-Decladinosyl-11,12dideoxy-6-O-[(quinolin-6-yl)-propen-3-yl]-3-oxo12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA

[0297] A mixture of intermediate 33 (0.150 g), palladium (II) acetate(0.019 g) and tri-o-tolylphosphine (0.051 g) in anhydrous DMF (2 mL) wasflushed with nitrogen. To this solution TEA (0.120 mL) and intermediate31 (0.210 g) were added. The reaction mixture was heated at 90° C. for24 h. The reaction mixture was diluted with EtOAc (10 mL), washed with a5% NaHCO₃ aqueous solution (5 mL) and brine (5 mL), dried over Na₂SO₄and concentrated under reduced pressure. The purification of the crudematerial by flash chromatography (eluting with: DCM/MeOH from 100/0 to96/4) gave a compound that was dissolved in MeOH (3 mL) and stirredovernight at room temperature. After evaporation of the solvent, thecrude material was purified by flash chromatography (eluting with:DCM/MeOH from 98/2 to 96/4) to give the title compound (0.015 g).

[0298]¹H-NMR (CDCl₃) δ: 8.85 (m, 1H), 8.15 (d, 1H), 8.06 (d, 1H), 7.89(d, 1H), 7.74 (d, 1H), 7.37 (m, 1H), 6.59 (d, 1H), 6.21 (m, 1H), 4.76(d, 1H), 3.99 (m, 2H), 3.30 (d, 1H), 3.16 (m, 1H), 2.70 (m, 1H), 1.85(m, 1H), 1.73 (m, 1H), 1.63 (s, 3H), 1.44 (s, 3H).

EXAMPLE 6(11S,21R)-3-Decladinosyl-11,12-dideoxy-6-O-[(quinolin-7-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA

[0299] A mixture of intermediate 33 (0.200 g), palladium (II) acetate(0.025 g) and tri-o-tolylphosphine (0.068 g) in anhydrous DMF (3 mL) wasflushed with nitrogen. To this solution TEA (0.160 mL) and intermediate32 (0.310 g) were added. The reaction mixture was heated at 90° C. for24 h. The reaction mixture was diluted with EtOAc (15 mL), washed with a5% NaHCO₃ aqueous solution (10 mL) and brine (10 mL), dried over Na₂SO₄and concentrated under reduced pressure. The purification of the crudematerial by flash chromatography (eluting with: DCM/MeOH from 100/0 to96/4) gave a compound that was dissolved in MeOH (5 mL) and stirredovernight at room temperature. After solvent evaporation, the crudematerial was purified by flash chromatography (eluting with: DCM/MeOHfrom 100/0 to 90/10) to give the title compound (0.006 g).

[0300]¹H-NMR (CDCl₃) δ: 8.88 (m, 1H), 8.11 (d, 1H), 7.98 (s, 1H), 7.79(s, 1H), 7.33 (m, 1H), 6.62 (d, 1H), 6.27 (m, 1H), 4.78 (m, 1H), 3.98(m, 2H), 2.70 (m, 1H), 1.84 (m, 1H), 1.70 (m, 1H), 1.63 (s, 3H), 1.44(s, 3H).

EXAMPLE 7(11S,21R)-3-decladinosyl-11,12-dideoxy-6-O-[(quinolin-7-yl)-propyl]-3-oxo-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA

[0301] To a solution of example 2 (0.015 g) in MeOH (1.5 mL), palladium(10 wt. % on carbon powder, 0.015 g) was added and the mixture stirredunder hydrogen atmosphere overnight. Filtration of the catalyst througha celite pad eluting with DCM (5 mL) and MeOH (5 mL) then purificationby flash chromatography (eluting with: DCM/MeOH 96/4) gave the titlecompound (0.007 g).

[0302]¹H-NMR (CDCl₃) δ: 8.80 (m, 1H), 8.06 (d, 1H), 8.02 (d, 1H), 7.80(d, 1H), 7.64 (t, 1H), 7.54 (t, 1H), 4.78 (m, 1H), 3.28 (m, 3H), 2.71(m, 2H), 1.85 (m, 1H), 1.65 (m, 1H), 1.63 (s, 3H), 1.30 (s, 3H).

EXAMPLE 8(11S,21R)-3-decladinosyl-11,12-dideoxy-6-O-[(quinolin-5-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonylmethylene]-erythromycinA

[0303] To a solution of example 4 (0.010 g) in a mixture of THF/water97/3 (2 mL) neutral activated aluminum oxide (0.040 g) was added and thereaction mixture stirred at 65° C. for 10 days. The mixture was filteredand the solid residue washed with EtOAc (3×5 mL) and DCM (3×5 mL).Solvent evaporation gave a crude material that was purified by flashchromatography (eluting with: DCM/MeOH from 100/0 to 98/2) to give thetitle compound (0.0015 g).

[0304]¹H-NMR (CDCl₃) δ: 8.92 (dd, 1H), 8.61 (d, 1H), 8.04 (d, 1H), 7.80(d, 1H), 7.73 (dd, 1H), 7.43 (dd, 1H), 7.11 (d, 1H), 6.05 (m, 1H),3.96−3.65 (m, 2H), 2.86 (m, 1H), 2.26 (m, 1H), 1.52 (s, 3H), 1.45 (s,3H).

EXAMPLE 9(11S,21R)-3-decladinosyl-11,12-dideoxy-6-O-[(quinolin-6-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonylmethylene]-erythromycinA

[0305] To a solution of example 5 (0.010 g) in a mixture of THF/water97/3 (2 mL) neutral activated aluminum oxide (0.040 g) was added and thereaction mixture stirred at 65° C. for 13 days. The mixture wasfiltered, the solid residue washed with EtOAc (3×10 mL) and DCM (3×10mL). Solvent evaporation gave a crude material that was purified byflash chromatography (eluting with : DCM/MeOH from 100/0 to 95/5) togive the title compound (0.0015 g).

[0306]¹H-NMR (CDCl₃) δ: 8.92 (dd, 1H), 8.61 (d, 1H), 8.04 (d, 1H), 7.80(d, 1H), 7.73 (dd, 1H), 7.43 (dd, 1H), 7.11 (d, 1H), 6.05 (m, 1H),3.96-3.65 (m, 2H), 2.86 (m, 1H), 2.26 (m, 1H), 1.53 (s, 3H), 1.42 (s,3H).

Pharmacy Examples

[0307] Tablets mg/tab Active ingredient 320 Lactose 150 Ethyl cellulose20 Sodium lauryl sulphate 7 Magnesium stearate 3 Tablet core 500

[0308] The active ingredient and the lactose are blended together andthen granulated using water as granulating fluid. The dried granules areblended with ethyl cellulose, sodium lauryl sulphate and magnesiumstearate and the tablet core formed using an appropriate punch. Thetablet may be coated using conventional technique and coatings.

Injection

[0309] The sterile vials were filled with the sterile active ingredient(500 mg). Purge the vial head space with sterile nitrogen; close thevials using rubber and metal overseals. The product may be constitutedby dissolving in water for injection(10 ml) or other suitable sterilevehicle for injection shortly before administration.

Activity Data

[0310] The value of MIC (microbial inhibition concentration), obtainedaccording to NCCLS (National Committee for Clinical LaboratoryStandards), of the preferred compounds of the invention againsterythromycin susceptible Streptococcus pneumoniae and Streptococcuspyogenes are less than or equal to 0.06 ug/ml.

[0311] In particular examples 2, 3, 5 and 6 showed MIC in the range0.1-64 ug/ml against erythromycin resistant Streptococcus pneumoniaestrains.

1. A compound of formula (I)

wherein R is hydrogen, cyano or NR₄R₅; R₁ is XR₆; R₂ is hydrogen or ahydroxyl protecting group; R₃ is hydrogen or halogen; R₆ is selectedfrom: optionally substituted phenyl; optionally substituted 5 or 6membered heteroaryl in which the 5-membered heteroaryl contains at leastone heteroatom selected from oxygen, sulphur or nitrogen and the6-membered heteroaryl group contains from 1 to 3 nitrogen atoms,optionally substituted 5-6 membered heterocyclic, optionally substituted9 to 10 membered fused bicyclic carbocyclic; or R₆ is an optionallysubstituted 9 or 10 membered fused bicyclic heterocyclic having at leastone heteroatom selected from oxygen, sulphur or nitrogen; X is a C₁₋₁₀alkylene, a C₃₋₁₀ alkenylene or a C₃₋₁₀ alkynylene chain wherein saidchains are: +P2 i) optionally interrupted by a bivalent radical groupselected from —N(R₅)—, —C(O)—, —S(O)n-, —N(R₅)C(O)—, —C(O)N(R₅)—, ii)optionally substituted by one or two groups selected from: C₁₋₄ alkyl,oxo, C₁₋₄ alkoxy, halogen, cyano, phenoxy, hydroxy, NR₄R₅; R₄ ishydrogen, C₁₋₄ alkyl or C(O)R₅; R₅ is hydrogen or C₁₋₄ alkyl; n is 0 oran integer from 1 to 2; and pharmaceutically acceptable salts andsolvates thereof.
 2. A compound as claimed in claim 1 wherein R₂ ishydrogen.
 3. A compound as claimed in claim 1 or 2 wherein R₃ ishydrogen or fluorine.
 4. A compound as claimed in any claims 1 to 3wherein R₆ is a group selected from phenyl, quinolinyl,pyridinyl-imidazolyl or pyridinyl-4-thiazolyl.
 5. A compound of formula(I) as claimed in any claims 1 to 4 wherein X a C₁₋₆ alkylene or C₃₋₆alkenylene chain, R₆ is a group selected from phenyl, quinolinyl,pyridyl-inidazolyl, pyridyl-4-thiazolyl and R₂, R₃, R₄ and R₅ arehydrogen.
 6. A compound selected from:(11S,21R)-3-Decladinosyl-11,12-dideoxy-6-O-[(quinolin-3-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA;(11S)-3-Decladinosyl-11,12-dideoxy-6-O-[(quinolin-3-yl)propen-3-yl]-3-oxo-12,11-[oxycarbonyl-methylene]-erythromycinA;(11S,21R)-3-Decladinosyl-11,12-dideoxy-6-O-[(quinolin-5-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA;(11S,21R)-3-Decladinosyl-11,12-dideoxy-6-O-[(quinolin-6-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-(cyano)-methylene]-erythromycinA;(11S,21R)-3-Decladinosyl-11,12-dideoxy-6-O-[(quinolin-7-yl)-propen-3-yl]-3-oxo-12,11-[oxycarbonyl-(cyano)methylene]-erythromycinA.
 7. A process for the preparation of a compound as claimed in claim 1which comprises: a) cyclisation of chlorine derivatives (IV), whereinR_(1a) has the meaning defined in claim 1 for R₁ or is a groupconvertible thereto, R₂, R₃ have the meanings defined in claim 1, R₁₀ isa cladinose derivative of formula (III) or hydroxy, R₁₁ is hydrogen orR₁₁ together R₁₀ is an oxygen atom,

to produce a compound of formula (I) wherein R is cyano; b) eliminationof the cyano group from a compound of formula (II), wherein R_(1a), R₁₀and R₁₁ have the meaning as defined for compounds of formula (IV), R₂,R₃ have the meanings defined in claim 1,

to produce compound of formula (I) wherein R is hydrogen; c) reactingamino compounds of formula (V) in which wherein R_(1a), R₁₀ and R₁₁ havethe meaning as defined for compounds of formula (IV), R₂, R₃ have themeanings defined in claim 1,

with a suitable alkylating agent of formula L-R₄ (VI), wherein R₄ isC₁₋₄ alkyl and L is a suitable leaving group to produce a compound offormula(I) wherein R₄ is C₁₋₄alkyl and R₅ is hydrogen or C₁₋₄alkyl; d)reacting amino compounds of formula (V) wherein R_(1a), R₁₀ and R₁₁ havethe meaning as defined for compounds of formula (II), R₂, R₃ have themeanings defined in claim 1, with an activated derivative of the acidHO(O)CR₅ (VI a) to produce a compound of formula (I) wherein R isNHR₄R₅, R₄ is C(O)R₅; e) cyclisation of compounds of formula (VII)wherein R₁₂ is a suitable nitrogen protecting group, R₂, R₃ have themeanings defined in claim 1, R_(1a), R₁₀ and R₁₁ have the meaningdefined in formula (IV),

in the presence of an organic base, followed by removal of the nitrogenprotecting group, to produce a compound of formula(I) wherein R is NH2;f) reacting a compounds of formula (I), wherein R_(1a), R₁₀ and R₁₁ havethe meaning as defined for compounds of formula (II), R₃ is hydrogen andR₂ is hydroxy protecting group, with a halogenating agent to produce acompound of formula(I) wherein R₃ is halogen; thereafter, if required,subjecting the resulting compound to one or more of the followingoperations: i) conversion of the group R_(1a) into the group R₁; ii)hydrolysis of the cladinose derivative (III); iii) conversion of the3-hydroxy group into the 3-oxo iv) removal of the protecting group R₂and v) conversion of the resultant compound of formula(I) into apharmaceutically acceptable salt and solvates thereof.
 8. A compound asclaimed in any claims 1 to 6 for use in therapy.
 9. The use of acompound as claimed in any claims 1 to 6 in the preparation of amedicament for use in the therapy of systemic or topical bacterialinfections in a human or animal body.
 10. The use of a compound asclaimed in any claims 1 to 6 for use in the treatment or prophylaxis ofsystemic or topical bacterial infections in a human or animal body. 11.A pharmaceutical composition comprising a compound as claimed in in anyclaims 1 to 6 in admixture with one or more pharmaceutically acceptablecarriers or excipients.
 12. A method for the treatment of the human ornon human animal body to combat bacterial infection comprisingadministration of an effective amount of a compound as claimed in anyclaims 1 to 6.